a) Field of the Invention
The present invention relates to pharmaceutical compositions and particularly to compositions for use in treating gastroesophageal and gastrointestinal irritations.
Esophageal pain, commonly referred to as heartburn, is symptomatic of gastric reflux. Gastric reflux occurs when small amounts of gastric juice and/or bile acids pass into the lower part of the esophagus and cause esophageal irritation. Typically, gastric reflux, which occurs after meals, especially large meals, is aggravated by bending over or lying down, and is a common occurrence in patients having a hiatal hernia, or a weakening of the esophageal sphincter. Severe episodes of gastric reflux may inflame the esophageal mucosa and lead to the more serious condition of reflux esophagitis in which severe damage or loss of squamous epithelium of the lower part of the esophagus may occur.
The invention relates to raft-forming preparations which are employed for the treatment and alleviation of painful conditions resulting from the reflux of gastric acid and bile into the esophagus, comprising aluminum hydroxide, xanthan gum and bicarbonate or carbonate, as the antacid and raft forming components.
b) Information Disclosure Statement
Basic metal salts and their use in antacid formulations are known in the art. Examples of metals known to form basic salts are alkali or alkaline earth metals and aluminum. The most commonly employed aluminum salts are the hydroxide, carbonate or phosphate. Examples of alkaline earth metals such as calcium are known, the use of calcium carbonate as an antacid either alone or in combination with other metal salts, such as magnesium carbonate and magnesium hydroxide is known. The use alkali metals, such as sodium as sodium bicarbonate is known in antacid formulations.
An approach to the problem of gastric reflux comprises the administration of a preparation which forms a gelatinous foam or raft which floats on the stomach contents. The foam-containing antacid precedes the stomach contents into the esophagus when reflux occurs and helps to protect the mucosa from further irritation. The gelatinous foam is formed by the combination of an acid insoluble gelatinous material entrapping CO.sub.2 gas. The present invention relates to improvements in formulation of preparations which are capable of forming such foams.
Antacid compositions which contain a gel-forming agent and an acid neutralizing agent are known (cf.N. Washington et al. Int. J. Pharm. 27, 1985, pp. 279-286 and N. Washington et al., Int. J. Pharm. 28, 1986, pp.139-143). The gel-forming agent in these known compositions is alginic acid, and they further contain sodium bicarbonate and usually at least one other acid neutralizing agent as well.
Typically when alginate-based calcium carbonate/sodium bicarbonate containing rafting antacids come into contact with the acid contents of the stomach the water insoluble calcium carbonate dissolves, liberating calcium ions which then react with alginate to form a gelatinous mass of calcium alginate. Much of the carbon dioxide liberated from the calcium carbonate and from the sodium bicarbonate becomes trapped in the mass causing it to rise as a `raft` of neutral gel which effectively impedes reflux. In severe cases this neutral gel itself may be refluxed into the esophagus, where it is said to protect the inflamed mucosa, allowing healing to take place and preventing further inflammation.
Several formulations have been developed in order to produce an antacid suspension with rafting properties, combining antacid placement in the upper stomach/lower esophagus with prolonged buffering ability to ensure that refluxed material is close to neutral pH. Heretofore known preparations used to create the aforementioned "rafts" comprise sodium bicarbonate and either solid compositions or liquid suspensions of alginic acid or its sodium salt. Exemplary of such prior art preparations include the product sold under the trade name GAVISCON (Marion Laboratories) and compositions described in U.S. Pat. No. 4,140,760.
GAVISCON is a pink, viscous, aniseed-flavored suspension. 10 ml of GAVISCON contains 500 mg sodium alginate, 267 mg sodium bicarbonate and 160 mg calcium carbonate. The recommended dose is 10-20 ml four times a day, after meals and at bedtime, or as needed.
In addition certain compositions for raft forming antacids are disclosed in the following U.S. patents:
U.S. Pat. No. 5,112,813 issued to Rhone-Poulenc Rorer on May 12, 1992 describes a process for producing a viscosity-stable rafting antacid composition using potassium bicarbonate, magnesium carbonate, aluminum hydroxide, magnesium alginate and xanthan gum as a stabilizer.
U.S. Pat. No. 5,068,109 issued to Farina Foods on Nov. 26, 1991 describes an antacid composition with floating properties containing potassium bicarbonate, magnesium carbonate and pectin.
U.S. Pat. No. 5,036,057 issued to University of Melbourne on Jul. 30, 1991 describes a method of treating gastroesophageal reflux using a composition with rafting properties containing calcium carbonate, sodium bicarbonate, aluminum hydroxide or magnesium carbonate and sodium alginate.
U.S. Pat. No. 4,869,902 issued to Rorer Pharmaceutical Corporation on Sep. 26, 1989 describes a pharmaceutical composition for treatment of reflux using a composition with rafting properties containing calcium carbonate, sodium bicarbonate, aluminum hydroxide or magnesium carbonate and sodium alginate.
U.S. Pat. No. 4,744,986 issued to Rorer Pharmaceutical Corporation May 17, 1988 describes a pharmaceutical composition for treatment of reflux esophagitis with rafting properties containing potassium bicarbonate, magnesium carbonate, aluminum hydroxide, stabilizer and magnesium alginate.
U.S. Pat. No. 4,613,497 issued to Health Products Development, Inc. on Sep. 23, 1986 describes a dry, water-foamable pharmaceutical composition for a gastric antacid material producing rafting containing carrageenan, sodium bicarbonate, tartaric acid, calcium carbonate, aluminum hydroxide and magnesium hydroxide.
U.S. Pat. No. 4,465,667 issued to Aktielbolaget Hassle on Aug. 14, 1984 describes a processing for preparing gastric acid neutralizing agents having rafting properties containing magnesium carbonate, hexitol stabilized aluminum hydroxide, and hydrogenated glucose polymers.
U.S. Pat. No. 4,012,333 issued to Hercules Incorporated on Mar. 15, 1977 describes preparation of gels of beta-1,3-glucan-type polysaccharide by exposure to CO.sub.2 gas.
U.S. Pat. No. 4,140,760 issued to Reckitt & Colman Products Limited on Feb. 20, 1979 describes a pharmaceutical composition for treatment of reflux esophagitis with rafting properties containing potassium bicarbonate, magnesium carbonate, and sodium alginate.
U.S. Pat. No. 2,774,710 issued to Kenneth Thomson on Dec. 18, 1956 describes an antacid preparation combining known antacids and a composition producing a protective layer containing a guar gum.